Technical Field
The present invention generally relates to fluidic devices, such as microfluidic devices, and methods for manufacture and use of the same.
Description of the Related Art
Fluidic microcircuits are known in the art, and include mechanical systems such as piston driven devices, electrohydraulic systems such as electrokinetic pump and valve devices, and pneumohydraulic systems. Of these, those systems with pneumatic actuators and control surfaces have proven most practical in controlling microscale fluid flows.
One class of fluidic devices having a pneumatic interface is manufactured by Micronics, Inc. (Redmond, Wash.). Control of fluid flow in microfluidic channels is achieved with a MICROFLOW® system pneumatic controller, which operates millimeter-sized valves in a plastic cartridge according to programmable valve logic. Miniature diaphragms separate the pneumatic side and the hydraulic side of the cartridges; i.e., the valve diaphragms are interface elements for converting pneumatic control pulses into starting and stopping fluid flow. Cartridges are formed by building up laminations, layer by layer, with channels and chambers sealed between capping overlayers. All the diaphragms are formed of a single layer. In this way, complex fluidic circuits are formed. Pneumatic and hydraulic channels and chambers are formed such that the pneumatic workings and the hydraulic workings of the cartridge are separated by an elastomeric diaphragm layer. Diaphragms formed of polyurethane and PDMS have been favorites for this method. An unsolved problem is the ability to manufacture circuits in which the diaphragm material can be varied (e.g., breathable, chemically resistant, rupturable, elastomeric, inelastic, and so forth) according to the type or subtype of circuit element.
A second unsolved problem relates to the manufacturability of microcircuits having millimeter and sub-millimeter footprints. Miniaturization has proven a benefit, favoring development of devices having a higher density of circuit components per unit area, but valves and diaphragms at a millimeter or sub-millimeter scale have been difficult to realize by current production methods.
Micropumps
Miniature diaphragm pump elements, for example, are needed to achieve fullest benefit of fluidic microcircuitry technologies, which find numerous applications such as in diagnostics and in life sciences more generally. Diaphragm-driven pumps are advantageous because of their sanitary features, including the absence of mechanical seals and lubricant.
Although miniature pumps were generically disclosed by Wilding (for example in U.S. Pat. Nos. 5,304,487 and 5,498,392), the disclosures themselves were not sufficient to fully enable fluidic microcircuitry pumps and valves. Cited by Wilding was Van Lintel [1988, “A Piezoelectric Micropump Based on Micromachining of Silicon,” Sensors and Actuators, 15:153-167], which relates to pumps microfabricated from silicon. Silicon-based microelectromechanical (MEMS) structures are not generally compatible with modern plastic devices.
There has been greater interest in elastomeric diaphragm materials because of the higher compression ratio and larger displacement volume, which offers the advantage of self-priming in fluidic operations. For example, polydimethylsiloxane (PDMS) and silicones generally readily form thin sheets or articulated blocks and are used as diaphragm materials. Latex rubber and amorphous polyurethanes have also been used. Elastomeric materials that obey Hooke's law have the advantage that the diaphragm returns to its original shape in the relaxed state, but this is advantageous only for some applications, and can be associated with lack of chemical resistance.
Microvalves
Representative art related to valves includes U.S. Pat. No. 4,304,257 (the '257 valve), in which a soft, resilient, polyurethane sheet is clamped over flow channels formed in a hard acrylic body. A fluid path between two discontinuous fluid channels is opened and closed by actuating pistons which mechanically flex a part of the sheet. A tenting action on the sheet is associated with valve opening; valve closing is associated with spring return of the resilient sheet to a closed position. The sheet is flexed mechanically between the two positions by a solenoid-operated rod having an embedded attachment to the sheet over the valve seat, such that the sheet contacts the seat when closed and the sheet is pulled into an aperture overlying the valve seat to open the valve.
According to the teachings of U.S. Pat. No. 4,848,722, the '257 valve has several disadvantages. In addition to delicacy of mechanical solenoid operation and need for fine adjustment, the membrane is subjected to great stresses with the risk of permanent stretch (i.e., permanent deformation or pinching past its yield point). By virtue of the concave contact surface for the membrane, the sealing area is maximized, but disadvantageously, a non-zero and significant volume of the valve cavity must be filled before fluid begins to flow.
In expired U.S. Pat. No. 4,848,722 (the '722 valve), a pressure or vacuum source is used to urge a flexible sheet such as biaxially oriented polyethylene terephthalate (boPET) into a stop-flow position in which apertures formed by the channels (3,4) in the valve seat are closed and an open position in which the apertures are fluidly confluent. The step land (FIG. 9: 62) of the valve seat is contacted by sheet (8) when the valve is closed. The sheet is glued to the pneumatic side of the valve.
U.S. Pat. No. 4,869,282 describes a micromachined valve having a diaphragm layer sandwiched between two rigid layers forming the valve cavity. The diaphragm layer is formed of polyimide, which is deflected by an applied pneumatic pressure in a control circuit to close the valve. Diaphragm motion is limited to avoid overstressing the polyimide layer.
Expired U.S. Pat. No. 5,660,370 (the '370 valve) describes a valve (FIG. 1: 1) having flexible diaphragm (2) and flat valve seat formed of a rigid layer in which two holes are formed, each hole defining an opening to a fluidic channel (3,4) in an underlying layer, where the holes are separated by a valve sill. The diaphragm is made of polyurethane or silicone. The valve (5) is opened by pneumatically exercising the diaphragm. To avoid the tendency of the sheet to become stressed beyond its yield point, a flat valve seat is used to minimize the required range of diaphragm motion. This also reduces the deadspace volume of the valve.
A similar structure is seen in U.S. Pat. No. 5,932,799 to YSI Inc., which teaches a fluidic microcircuitry analyzer having a plurality of polyimide layers, preferably KAPTON® film, directly bonded together without adhesives and a flexible pneumatically actuated diaphragm member for controlling fluid flow.
WO Publ. No. 2002/081934 to Micronics, Inc., published Oct. 17, 2002, describes a laminated valve having an elastomeric diaphragm. These valves, which were termed “peanut valves”, admit fluid across the valve sill under negative pressure, and are closed when positively pressurized. Advantageously, the valve cavity is formed with a contoured waist to minimize deadspace volume.
U.S. Pat. No. 7,445,926 to Mathies describes a laminate with a flexible diaphragm layer sandwiched between hard substrates. Pneumatic channels and fluid channels are formed on opposite sides of the diaphragm layer (cf., FIG. 1 of the reference), so that the diaphragm is the active valve member. The diaphragm material disclosed is a 254 micrometer PDMS membrane. The valve body is typically a solid such as glass.
US Pat. Appl. Nos. 2006/0275852 and 2011/0207621 to Montagu describe a fluidic cartridge for biological assays. The cartridge includes a molded body defining flow passages. A latex diaphragm and a canned diaphragm pump are shown (cf., FIG. 5 of the reference). The “rolling elastic diaphragm pump” member (3) is inserted into the cartridge as a preformed subassembly and is commercially available (Thomas Pumps, Model 1101 miniature compressor, Sheboygan, Wis. 53081). Valves are mechanically actuated using a stepper motor. Thus the valves have the disadvantage of requiring sensitive and meticulous adjustment for proper operation.
Other elastomeric valve and pump constructs are known. Examples of silicone valve construction include U.S. Pat. Nos. 5,443,890, 6,793,753, 6,951,632 and 8,104,514, all of which illustrate soft lithographic processes (cf., U.S. Pat. Nos. 7,695,683 and 8,104,497) for forming valves and pumps. PDMS may be used to form diaphragms and pump bodies. Latex rubber and amorphous polyurethanes have also been used as diaphragm materials, but chemical resistance may not be sufficient for some applications.
While not limiting, examples of diaphragm materials having properties that have not been exploited for pneumohydraulic circuits include members that are gas permeable and liquid impermeable after wetting. Diaphragm members that are elastic and breathable are not known in the field of fluidic microcircuitry technology. Diaphragm members having solvent resistance and capable of being shaped into form-in-place diaphragms are not known. Other potential diaphragm materials have not been considered because means for independently selecting a diaphragm material for each class of fluidic element (such as valve, pump, reservoir, and so forth) are not known.
Advantageously, a gas-permeable diaphragm that retains its breathability after wetting would permit use of diaphragms in dead-ended fluidic circuits. Advantageously, a solvent-resistant diaphragm that yields to form a pre-shaped diaphragm member has application in valves used for pumping suspensions of particulates, and for replacing polyurethane diaphragms which leak when exposed to caustics, chaeotropes, or solvents, thus permitting use of solvents such as ethanol, formamide and dimethylsulfoxide for reducing temperature requirements during PCR, while not limited thereto.
Materials suited for one such application may be unsuited for another. As a first example, valve diaphragms may not be workable if fabricated from a microporous gas-permeable film, whereas vents require microporosity. Similarly, diaphragms requiring elasticity may not be readily substituted by diaphragms having a low yield point. Optimization of materials for particular classes of fluidic elements offers an advantage only if each class of fluidic elements can be optimized independently. Selected embodiments of the inventions cannot be realized without methods of manufacture which selectably incorporate an assortment or mixed palette of advanced diaphragm materials into the pump, valve, filter, vent and cuvette membranes of individual cartridges, where each class of fluidic elements is represented by a distinct and dissimilar diaphragm material. The various diaphragm materials are generally made of thin films.
The engineering of both valve and pump diaphragms can benefit from a manufacturing method that permits assembly of fluidic devices using thin films selectable from a list of materials. Conventional glue in place methods are not well suited to mass production and have raised technical barriers to further miniaturization and increased density of circuit elements. Given the unique advantages of the combinations disclosed herein, a process is needed to manufacture a fluidic circuit in which each diaphragm member of the fluidic circuit is independently selected from a plurality of available materials according the functional requirements of each individual circuit element. Currently available methods do not permit mass production of devices comprised of multiple diaphragm materials on a single cartridge at the manufacturing scale needed to satisfy the expected market growth in use of fluidic devices, such as for diagnostic assays.
While progress has been made, there is a need in the art for improved fluidic devices, such as microfluidic devices, The present invention provides this and related advantages.